The purpose of this proposal is to investigate the effects of neurotoxic injury to the nigrostriatal dopaminergic system on the serotonergic system to understand how these alterations influence affective and motor dysfunction in Parkinson's Disease (PD). It is becoming evident that PD is not simply a motor disorder. Patients with PD are significantly more depressed than other similarly-disabled patients. At the molecular level, interactions between the serotonergic and dopaminergic systems contribute to affective disorders including anxiety and depression, and may underlie the close relationship between affective and motor dysfunction in PD. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse will be used here as a model since there is return of striatal DA and intrinsic plasticity of the dopaminergic system over time. In the proposed studies, we will test the hypothesis that there are dynamic behavioral, molecular, and morphological alterations in the serotonergic system in the MPTP-lesioned mouse. Mice will receive MPTP or saline and analyzed at post-lesioned days 5 (early, acute depletion when MPTP-induced cell death is complete), and 35 (partial DA recovery). Analyses will include (i) depression and anxiety; (ii) striatal dopamine and serotonin by HPLC, (iii) cell counts of dopaminergic neurons in substantia nigra pars compacta and serotonergic neurons in the dorsal raphe, and (iv) mRNA expression of 5-HT receptors 1a, 1b, 2a, and 2c in midbrain, striatum, limbic system, and frontal cortex. We hypothesize that there is an acute increase in the serotonergic system after MPTP-lesioning that is then down-regulated in an attempt to facilitate dopaminergic neurotransmission. As DA returns 5-HT neurotransmission normalizes. Furthermore, increases or decreases in the 5-HT system drive changes in anxiety and depression. A secondary goal of our studies is to determine the role of steroid hormones in susceptibility to affective disorders in PD. We hypothesize that castration will increase anxiety and depression in the MPTP-lesioned mouse. Working with Dr. Michael Jakowec of the Department of Neurology at the Keck School of Medicine of USC, Dr. Wood will receive training in molecular techniques for measurement of serotonin and its receptors. In addition, she will spend time in the laboratory of Dr. George F. Koob at The Scripps Research Institute to learn additional approaches to study anxiety and depression in mice. [unreadable] [unreadable] [unreadable]